Pembrolizumab plus neoadjuvant chemotherapy in early-stage, high-risk ER+/HER2- breast cancer leads to a statistically significant increase in pathological complete response.

Although patients with early-state ER+/HER2- breast cancer generally have a better prognosis than those with other breast cancer subtypes, a high-risk subpopulation benefits from NAC. For this subpopulation, the pathological complete responses (pCRs) after neoadjuvant chemotherapy (NAC) range from 0% to 18% [1]. In triple-negative breast cancer (TNBC), the addition of pembrolizumab to NAC and continued as adjuvant therapy increased the pCR and improved event-free survival (EFS) [2]. The phase 3 KEYNOTE-756 trial (NCT03725059) now explores the efficacy and safety of adding pembrolizumab to current and subsequent adjuvant pembrolizumab in patients with early-stage high-risk ER+/HER2-breast cancer. The final pCR results were presented by Dr. Fatima Cardoso (Champalimaud Clinical Centre, Portugal) [3].

In KEYNOTE-756, 1278 participants (grade 3 ER+/HER2-, T1c-2 N1–2 or T3–4 N0–2) were randomly assigned 1:1 to receiving NAC with pembrolizumab or placebo, followed by surgery and adjuvant pembrolizumab or placebo. The primary endpoints of the study are pCR and EFS. Results for EFS are not yet mature.

Progression (and discontinuation) during the neoadjuvant treatment was rare in both arms (2.2% in the pembrolizumab arm and 2.0% in the placebo arm). Adding pembrolizumab to NAC significantly improved pCR: 24.3% versus 15.6% in the placebo arm (P=0.00005). A pCR benefit from pembrolizumab was observed in all predefined subgroups, including PD-L1 status. In particular, in participants with ER-low (<10%) tumors, the benefit of pembrolizumab increased compared with NAC alone. “This particular finding fits in with the idea that ER-low tumors behave more like TNBC,” said Dr. Cardoso.

Overall, adding pembrolizumab to NAC did not significantly increase adverse event rates (52.5% vs 46.4% grade 3–5, pembrolizumab vs placebo arm). Immune-mediated adverse events were observed in 32.8% of pembrolizumab-treated patients (7.1% grade 3–5) with hypothyroidism and hyperthyroidism being most prominent.

“The addition of pembrolizumab to neoadjuvant chemotherapy in participants with early-stage, high-risk ER+/HER2- breast cancer leads to a statistically significant increase in pCR regardless of PD-L1 status,” concluded Dr. Cardoso.

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